Nicotine addiction continues to be the main preventable cause of death in developed countries, with an estimated 435,000 premature deaths in the U.S. Despite the availability of effective pharmacotherapies, 70 to 90% of smokers who attempt to quit resume smoking within a year of treatment. Women may have greater difficulty achieving and sustaining abstinence from smoking, as the ratio of former smokers to ever smokers (quit ratio) is lower in women (55.2%) than in men (59.2%). Women, compared to men, are more vulnerable to the complications of smoking, most notably lung cancer. In the US, lung cancer kills more women than breast and colon cancer combined. These findings support the need for effective treatments tailored for female smokers. One such approach may include use of progesterone to augment currently available smoking cessation treatments. Data from clinical studies suggest that in women with regular menstrual cycles, those who try to quit smoking when endogenous plasma progesterone levels are high, have a lower risk of relapse to smoking than those who try to quit when progesterone levels are low. Work from our group points to a potential therapeutic role for progesterone, in that progesterone attenuates both craving for cigarettes and the pleasurable effects of smoking among recently abstinent female smokers. Taken together, these findings led us to hypothesize that progesterone may augment the efficacy of smoking cessation treatments in regularly cycling women. This proof-of-concept study will test the safety, tolerability, and effectiveness of progesterone treatment, compared to placebo, in combination with transdermal nicotine patch (TNP) for smoking cessation in regularly cycling women. We propose an 8-week, pilot, clinical trial in which 50 smokers will be randomized to progesterone (200 mg twice daily) or placebo. All participants will also receive TNP and behavioral treatment for smoking cessation during study participation. Smokers will attempt to quit smoking one week after initiation of progesterone and TNP treatment. The main outcome measures will be the prolonged and 7-day point prevalence of smoking abstinence at the end of treatment and at 1- and 3-month follow-up time points. Progesterone, in contrast to the more commonly used synthetic progestins, is a natural hormone with excellent safety profile and its use as a novel smoking cessation medication in women is highly feasible.